Human Papillomavirus and Vaccination

Abstract

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States. Modeling estimates suggest that more than 80% of sexually active women will have acquired genital HPV by age 50 years. Although most infections are transient and asymptomatic, persistent infection with high-risk types of HPV can lead to precancerous lesions and progress to cancer. In June 2006, the US Food and Drug Administration licensed the first vaccine to prevent cervical cancers and other diseases in women. This quadrivalent vaccine protects against HPV-6, HPV-11, HPV-16, and HPV-18, which are responsible for 70% of cervical cancers and 90% of genital warts. Several studies have been published examining the vaccine's efficacy, duration, immunogenicity, and safety. Questions and controversy remain regarding mandatory vaccination, need for booster doses, and cost-effectiveness. Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States. Modeling estimates suggest that more than 80% of sexually active women will have acquired genital HPV by age 50 years. Although most infections are transient and asymptomatic, persistent infection with high-risk types of HPV can lead to precancerous lesions and progress to cancer. In June 2006, the US Food and Drug Administration licensed the first vaccine to prevent cervical cancers and other diseases in women. This quadrivalent vaccine protects against HPV-6, HPV-11, HPV-16, and HPV-18, which are responsible for 70% of cervical cancers and 90% of genital warts. Several studies have been published examining the vaccine's efficacy, duration, immunogenicity, and safety. Questions and controversy remain regarding mandatory vaccination, need for booster doses, and cost-effectiveness. Genital human papillomavirus (HPV) is the most common sexually transmitted infection in the United States; an estimated 6.2 million new infections occur each year.1National Cancer Institute, US National Institutes of Health Human papillomaviruses and cancer: questions and answers.http://www.cancer.gov/cancertopics/factsheet/Risk/HPVGoogle Scholar, 2US Food and Drug Administration FDA licenses new vaccine for prevention of cervical cancer and other diseases in females caused by human papillomavirus: rapid approval marks major advancement in public health. FDA News 2006 June 8.http://www.fda.gov/bbs/topics/NEWS/2006/NEW01385.htmlGoogle Scholar Although most infections are transient and asymptomatic, persistent infections with high-risk types of HPV can lead to cervical and anogenital cancers. Despite the decline in deaths due to cervical cancer in the United States since the widespread institution of Papanicolaou (Pap) testing, an estimated 11,070 new cases of invasive cervical cancer will be diagnosed and 3870 women will die of cervical cancer during 2008.3American Cancer Society Detailed guide: cervical cancer: what are the key statistics about cervical cancer? Revised Aug 4, 2006.http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_cervical_cancer_8.asp?sitearea=Google Scholar Worldwide, cervical cancer remains a leading cause of death, with half a million new cases and a quarter of a million deaths each year.1National Cancer Institute, US National Institutes of Health Human papillomaviruses and cancer: questions and answers.http://www.cancer.gov/cancertopics/factsheet/Risk/HPVGoogle Scholar, 2US Food and Drug Administration FDA licenses new vaccine for prevention of cervical cancer and other diseases in females caused by human papillomavirus: rapid approval marks major advancement in public health. FDA News 2006 June 8.http://www.fda.gov/bbs/topics/NEWS/2006/NEW01385.htmlGoogle Scholar, 4Saslow D Castle PE Cox JT Gynecologic Cancer Advisory Group et al.American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors.CA Cancer J Clin. 2007; 57: 7-28Crossref PubMed Scopus (444) Google Scholar, 5Pagliusi S World Health Organization Human papillomavirus infection and cervical cancer.http://www.who.int/vaccine_research/diseases/hpv/en/Google Scholar Hence, the advent of a vaccine against the HPV virus has stirred much excitement as well as debate. Human papillomaviruses are small, nonenveloped, double-stranded DNA viruses; their 8-kB circular genome encodes the encapsulating structural proteins L1 and L2, as well as several early genes that enable viral transcription and replication and interact with the host genome. Approximately 100 types of HPV have been identified; those that infect the genital area have a predilection for mucous membranes. The low-risk types can cause benign or low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis (RRP). The high-risk types can cause low-grade and high-grade cervical cell abnormalities that are precursors to cervical and anogenital cancers. Most HPV infections are transient and asymptomatic; they can be associated with mild cytologic abnormalities but, in general, cause no clinical problems. Of new infections, 70% clear within 1 year, and 90% clear within 2 years,6Markowitz LE Dunne EF Saraiya M Lawson HW Chesson H Unger ER Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56 (Accessed Apr 28, 2008.): 1-24http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htmPubMed Google Scholar with mean duration of 8 months.7Ho GY Bierman R Beardsley L Chang CJ Burk RD Natural history of cervicovaginal papillomavirus infection in young women.N Engl J Med. 1998; 338: 423-428Crossref PubMed Scopus (2136) Google Scholar However, persistent infection with high-risk types of HPV can progress to a precancerous lesion and eventually to cancer. Since the 1950s, the number of deaths due to cervical cancer in the United States has decreased by more than 70% and continues to decline by nearly 4% a year,3American Cancer Society Detailed guide: cervical cancer: what are the key statistics about cervical cancer? Revised Aug 4, 2006.http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_cervical_cancer_8.asp?sitearea=Google Scholar with widespread use of Pap testing. This decrease has been observed primarily in squamous cell cancers rather than adenocarcinomas, which are more difficult to detect with Pap tests. The clinical sequelae of HPV infection are not limited to cervical cancer and its precursor lesions; they have also been associated with several other types of squamous cell carcinomas and their precursors at different sites. A recent study reported further evidence of an association between HPV and oropharyngeal cancer that was independent of tobacco and alcohol use (with HPV-16 found in 72% of 60 oropharyngeal cancers sampled) and suggested an association with sexual behavior.8D'Souza G Kreimer AR Viscidi R et al.Case-control study of human papillomavirus and oropharyngeal cancer.N Engl J Med. 2007; 356: 1944-1956Crossref PubMed Scopus (2084) Google Scholar Also caused by HPV are anogenital warts (condylomas), approximately 90% of which are associated with HPV-6 and HPV-11.4Saslow D Castle PE Cox JT Gynecologic Cancer Advisory Group et al.American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors.CA Cancer J Clin. 2007; 57: 7-28Crossref PubMed Scopus (444) Google Scholar Infection with these low-risk HPV types rarely results in RRP, a disease that is characterized by recurrent warts or papillomas in the upper respiratory tract, particularly the larynx, and that is associated with extensive morbidity (Table 1).TABLE 1Clinical Sequelae of Infection With HPVaHPV = human papillomavirus; NA = not available.LesionAttributable to oncogenic HPV (%)Cervical cancers100bHPV-16 and HPV-18 account for 70% of cases.Anogenital cancers Anal90 Vulvar40 Vaginal40 Penile40Oropharyngeal cancers12Anogenital warts (condyloma)90cHPV-6 and HPV-ll.Recurrent respiratory papillomatosisNAdMainly HPV-6 and HPV-11.a HPV = human papillomavirus; NA = not available.b HPV-16 and HPV-18 account for 70% of cases.c HPV-6 and HPV-ll.d Mainly HPV-6 and HPV-11. Open table in a new tab Genital HPV infection is transmitted primarily by genital contact. Sexual activity remains the most consistent predictor of infection. In a study of women aged 18 to 25 years, HPV infection was found in 14.3% of women with 1 lifetime sex partner, in 22.3% of women with 2 lifetime sex partners, and in 31.5% of women with more than 3 lifetime sex partners.6Markowitz LE Dunne EF Saraiya M Lawson HW Chesson H Unger ER Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56 (Accessed Apr 28, 2008.): 1-24http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htmPubMed Google Scholar, 9Manhart LE Holmes KK Koutsky LA et al.Human papillomavirus infection among sexually active young women in the United States: implications for developing a vaccination strategy.Sex Transm Dis. 2006; 33: 502-508Crossref PubMed Scopus (122) Google Scholar In the 2002 National Survey of Family Growth, 24% of female respondents in the United States were sexually active by age 15 years, 40% by age 16 years, and 70% by age 18 years. The 2005 Youth Behavioral Risk Survey indicated that 3.7% of female students are sexually active before age 13 years. Of those sexually active, 5.7% of 9th-grade female students and 20.2% of 12th-grade female students had had at least 4 sex partners.6Markowitz LE Dunne EF Saraiya M Lawson HW Chesson H Unger ER Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56 (Accessed Apr 28, 2008.): 1-24http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htmPubMed Google Scholar Acquisition of HPV infection occurs soon after onset of sexual activity. 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 inter-course and more than 50.0% by 4 years. Of the 6.2 million new HPV infections each year, 74% occur among those aged 15 to 24 years. Modeling estimates suggest that more than 80% of sexually active women will have acquired genital HPV by age 50 years. In a study by Dunne et al10Dunne EF Unger ER Sternberg M et al.Prevalence of HPV infection among females in the United States.JAMA. 2007; 297: 813-819Crossref PubMed Scopus (1165) Google Scholar of population prevalence, overall prevalence of HPV (any type) was high at 26.8% in female participants aged 14 to 59 years, with nearly half of the cases occurring in those aged 20 to 24 years; however, combined prevalence of the 4 types (HPV-6, HPV-11, HPV-16, and HPV-18) targeted by the new vaccine was lower than expected at 3.4%. Human papillomavirus infection is also common among men, with a prevalence of more than 20% among heterosexual men.6Markowitz LE Dunne EF Saraiya M Lawson HW Chesson H Unger ER Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56 (Accessed Apr 28, 2008.): 1-24http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htmPubMed Google Scholar If cumulative incidence rather than prevalence data were considered, these numbers might be even higher. A few prospective studies have shown that condoms help prevent genital HPV infection. For example, a study among newly sexually active college women showed that consistent and correct condom use reduced HPV infection by 70%.11Winer RL Hughes JP Feng Q et al.Condom use and the risk of genital human papillomavirus infection in young women.N Engl J Med. 2006; 354: 2645-2654Crossref PubMed Scopus (528) Google Scholar Abstaining from sexual activity completely is the surest way to prevent infection. On June 8, 2006, the US Food and Drug Administration licensed the quadrivalent HPV vaccine by Merck and Co., Inc. Recombinant DNA technology is used to express the L1 major capsid protein of HPV in yeasts (Saccharomyces cerevisiae), which self-assemble to form empty shells resembling a virus, called viruslike particles (VLPs). The VLPs have the same outer L1 protein coat as HPV but contain no genetic material. The vaccine uses these VLPs as antigens to induce a strong protective immune response; if an exposure occurs, the vaccinated person's antibodies against the L1 protein will coat the virus and prevent it from releasing its genetic material. Each 0.5-mL dose contains HPV-6, HPV-11, HPV-16, and HPV-18 L1 proteins. Available as a sterile suspension for injection in a single-dose vial or a prefilled syringe, the vaccine should be shaken well and administered intramuscularly into the deltoid muscle of the upper arm or higher anterolateral thigh as 3 separate 0.5-mL doses at 0, 2, and 6 months, with minimum intervals of 4 weeks between doses 1 and 2 and 12 weeks between doses 2 and 3. Four randomized, double-blind, placebo-controlled studies evaluated the efficacy of the HPV vaccine. A phase 2 study of a monovalent HPV-16 vaccine (protocol 005) and a phase 2 study of quadrivalent HPV-6/11/16/18 vaccine (protocol 007) evaluated the efficacy of the vaccine using an end point of persistent infection. Two phase 3 studies of the quadrivalent HPV vaccine (protocols 013 and 015) evaluated the efficacy of the vaccine on clinical lesions. Protocol 005 enrolled 2392 female participants aged 16 to 23 years (mean age, 20 years; 75.8% white) from 16 centers in the United States between October 1998 and November 1999; study participants were randomized to receive 3 doses of either placebo (1198 participants) or HPV-16 VLP vaccine (1194 participants). When persistent HPV-16 infection was taken as the primary end point, vaccine efficacy was shown to be 100% after median follow-up of 17.4 months.12Koutsky LA Ault KA Wheeler CM Proof of Principle Study Investigators et al.A controlled trial of a human papillomavirus type 16 vaccine.N Engl J Med. 2002; 347: 1645-1651Crossref PubMed Scopus (1563) Google Scholar A follow-up study 3.5 years after vaccination showed the vaccine to provide 100% protection against HPV-16-related cervical intraepithelial neoplasia (CIN) 2 and 3; efficacy against persistent infection decreased slightly to 94% (95% confidence interval [CI], 88%-98%).13Mao C Koutsky LA Ault KA et al.Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial.Obstet Gynecol. 2006; 107: 18-27Crossref PubMed Scopus (442) Google Scholar Protocol 007 assessed the efficacy of the quadrivalent vaccine targeting HPV-6, HPV-11, HPV-16, and HPV-18 in 1158 female participants aged 16 to 23 years (mean age, 20; 78% white) randomized to receive vaccine (277 participants) or placebo (275 participants).14Villa LL Costa RL Petta CA et al.Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial.Lancet. 2005; 6: 271-278Abstract Full Text Full Text PDF Scopus (1427) Google Scholar Combined incidence of persistent infection with HPV-6, HPV-11, HPV-16, or HPV-18 or associated cervical or genital disease, the primary end point of the study, decreased by 90% (95% CI, 71%-97%, P<.0001) in the vaccinated group. Interim analysis from this study14Villa LL Costa RL Petta CA et al.Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial.Lancet. 2005; 6: 271-278Abstract Full Text Full Text PDF Scopus (1427) Google Scholar established the vaccine dosage used in the phase 3 studies. Once made available by the Centers for Disease Control and Prevention, the interim analyses from these larger, international phase 3 trials (including approximately 1.5 years of follow-up data) were used as part of the application for vaccine licensure. Further analyses, including an additional year of follow-up from the interim analyses, were published in 2007, known as Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I15Garland SM Hernandez-Avila M Wheeler CM Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators et al.Quadrivalent vaccine against the human papillomavirus to prevent anogenital diseases.N Engl J Med. 2007; 356: 1928-1943Crossref PubMed Scopus (1560) Google Scholar and II.16The FUTURE II Study Group Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions.N Engl J Med. 2007; 356: 1915-1927Crossref PubMed Scopus (1722) Google Scholar In the ongoing, randomized placebo-controlled, double-blind FUTURE I trial, 5455 female participants aged 16 through 24 years (mean age, 20 years) were enrolled from 62 study sites in 16 countries from January 2002 through March 2003, randomized to receive vaccine (2723 participants) or placebo (2732 participants), and followed up for an average of 3 years after first vaccine dose. The vaccine showed 100% efficacy (95% CI, 94%-100%) against both cervical lesions and external anogenital and vaginal lesions in the per-protocol population. The term per-protocol population refers to participants who completed the vaccination regimen, did not violate protocol, were seronegative, and had negative findings on polymerase chain reaction for the HPV strains in the vaccine through 1 month after the third vaccine dose. In an unrestricted susceptible population that included all women who were seronegative and who had negative findings on polymerase chain reaction at baseline, some of whom might have violated protocol, vaccine efficacy was found to be 98% (95% CI, 92%-100%) against cervical lesions and 95% (95% CI, 87%-99%) against external anogenital and vaginal lesions. Vaccine efficacy was also estimated in an intention-to-treat population that included all participants who had undergone randomization regardless of their baseline HPV status, with efficacy of 55% (95% CI, 40%-66%) against cervical lesions and 73% (95% CI, 58%-83%) against external anogenital and vaginal lesions. A second intention-to-treat analysis was done to evaluate lesions associated with any HPV type; vaccine efficacy was found to be 20% (95% CI, 8%-31%) against cervical lesions and 34% (95% CI, 15%-49%) against external anogenital and vaginal lesions (Table 2). The study concluded that the quadrivalent vaccine significantly reduced the incidence of HPV-associated anogenital diseases in young women.15Garland SM Hernandez-Avila M Wheeler CM Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators et al.Quadrivalent vaccine against the human papillomavirus to prevent anogenital diseases.N Engl J Med. 2007; 356: 1928-1943Crossref PubMed Scopus (1560) Google ScholarTABLE 2Summary Results of FUTURE I TrialaAIS = adenocarcinoma in situ; CI = confidence interval; CIN = cervical intraepithelial neoplasia; FUTURE = Females United to Unilaterally Reduce Endo/Ectocervical Disease; HPV = human papillomavirus.VaccinePlaceboType of analysisNo. of participantsCasesNo. of participantsCases% Efficacy (95% CI)PrimarybEvaluated lesions associated with vaccine-type HPV. Per-protocol susceptible population Cervical lesions (CIN 1-3 or AIS)22410225865100 (94-100) External anogenital and vaginal lesions22610227960100 (94-100) Unrestricted susceptible population Cervical lesions (CIN 1-3 or AIS)2667226848998 (92-100) External anogenital and vaginal lesions2667426848195 (87-99) Intention-to-treat population Cervical lesions (CIN 1-3 or AIS)272371273215555 (40-66) External anogenital and vaginal lesions272328273210273 (58-83)Second intention-to-treatcEvaluated lesions associated with any HPV type. Cervical lesions (CIN 1-3 or AIS)272334273242120 (8-31) External anogenital and vaginal lesions2723104273215734 (15-49)a AIS = adenocarcinoma in situ; CI = confidence interval; CIN = cervical intraepithelial neoplasia; FUTURE = Females United to Unilaterally Reduce Endo/Ectocervical Disease; HPV = human papillomavirus.b Evaluated lesions associated with vaccine-type HPV.c Evaluated lesions associated with any HPV type. Open table in a new tab FUTURE II examined vaccine efficacy against high-grade cervical lesions associated with HPV-16 and HPV-18. In this large, randomized placebo-controlled, double-blind trial, 12,167 female participants aged 15 through 26 years (mean age, 20 years) at 90 study sites in 13 countries were enrolled from June 2002 through May 2003, randomized to receive vaccine (6087 participants) or placebo (6080 participants), and followed up for an average of 3 years after the first vaccine dose. Similarly, in the per-protocol susceptible population, vaccine efficacy against CIN 2 and 3 or adenocarcinoma in situ was high at 98% (95% CI, 86%-100%). Vaccine efficacy was 95% (95% CI, 85%-99%) in the unrestricted susceptible population, 44% (95% CI, 26%-58%) in the intention-to-treat population, and 17% (95% CI,1%-31%) in the second intention-to-treat analysis. When administered to those who had not been previously exposed to either HPV-16 or HPV-18, the HPV vaccine was highly effective in preventing related CIN 2 and 3 and adenocarcinoma in situ (Table 3).16The FUTURE II Study Group Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions.N Engl J Med. 2007; 356: 1915-1927Crossref PubMed Scopus (1722) Google Scholar In other words, the quadrivalent vaccine is prophylactic, not therapeutic. No evidence exists of protection against disease caused by vaccine types for which participants had positive results on polymerase chain reaction at baseline. Participants with positive results to 1 or more vaccine HPV types before vaccination were protected against disease caused by the other vaccine types.TABLE 3Summary Results of FUTURE II TrialaAIS = adenocarcinoma in situ; CI = confidence interval; CIN = cervical intraepithelial neoplasia; FUTURE = Females United to Unilaterally Reduce Endo/Ectocervical Disease; HPV = human papillomavirus.VaccinePlaceboType of analysisNo. of participantsCasesNo. of participantsCases% Efficacy (95% CI)PrimarybEvaluated lesions associated with HPV-16, HPV-18, or both. Per-protocol susceptible population CIN 2 and 3 or AIS5305152604298 (86-100) Unrestricted susceptible population CIN 2 and 3 or AIS5865358636295 (85-99) Intention-to-treat population CIN 2 and 3 or AIS608783608014844 (26-58)Second intention-to-treatcEvaluated lesions associated with any HPV type. CIN 2 and 3 or AIS6087219608726617 (1-31)a AIS = adenocarcinoma in situ; CI = confidence interval; CIN = cervical intraepithelial neoplasia; FUTURE = Females United to Unilaterally Reduce Endo/Ectocervical Disease; HPV = human papillomavirus.b Evaluated lesions associated with HPV-16, HPV-18, or both.c Evaluated lesions associated with any HPV type. Open table in a new tab Antibody titers of HPV-16 gradually decline after the third dose but appear to plateau by 24 months. At 36 months, anti-HPV-16 geometric mean titers in vaccinees remained higher than those in the placebo group who were seropositive at baseline (vaccination produced antibody titers higher than those after natural infection).17Villa LL Ault KA Giuliano AR et al.Immunologic responses following administration of a vaccine targeting human papillomavirus types 6, 11, 16, and 18.Vaccine. 2006 Jul 7; 24 (Epub 2006 May 15.): 5571-5583Crossref PubMed Scopus (416) Google Scholar No minimum protective titer has been determined. In a combined analysis of all participants through year 3 and a subset through 60 months, efficacy against vaccine-HPV-type persistent infection or disease was 95.8% (95% CI, 83.8%-99.5%) and efficacy against vaccine-type-related CIN or external genital lesions was 100% (95% CI, 12.4%-100%).6Markowitz LE Dunne EF Saraiya M Lawson HW Chesson H Unger ER Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56 (Accessed Apr 28, 2008.): 1-24http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htmPubMed Google Scholar, 18Villa LL Costa RL Petta CA et al.High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine though 5 years of follow-up.Br J Cancer. 2006 Dec 4; 95 (Epub 2006 Nov 21.): 1459-1466Crossref PubMed Scopus (751) Google Scholar Longer follow-up studies are under way. To evaluate how the vaccine would perform in younger patients, immunogenicity studies in female children aged 9 to 15 years were conducted.6Markowitz LE Dunne EF Saraiya M Lawson HW Chesson H Unger ER Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56 (Accessed Apr 28, 2008.): 1-24http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htmPubMed Google Scholar, 19Gardasil [human papillomavirus quadrivalent (types 6,11,16,18) vaccine, Recombinant] [package insert]. Merck & Co, Whitehouse Station, NJ2006http://www.fda.gov/cber/label/gardasilLB.pdfGoogle Scholar Anti-HPV responses in these patients were no lower after the third dose than those of female patients aged 16 to 26 years. In fact, at month 18, anti-HPV geometric mean titers in the younger patients remained 2 to 3 times higher than those in the older patients. Safety data on quadrivalent HPV vaccine are available from 7 clinical trials including 11,778 vaccine recipients and 9686 placebo recipients aged 9 to 26 years. Additional details were collected in a subset of patients randomized to receive either vaccine (5088 patients) or placebo (3790 patients) using report cards for 14 days after each injection. Injection site pain was the most common adverse event (in 83.9% of vaccinees vs 75.4% receiving aluminum-containing placebo and 48.6% receiving saline placebo), followed by swelling (25%) and erythema (25%). Common systemic adverse effects included fever, nausea, and fainting, with similar occurrences in both vaccine and control groups. Most adverse events were mild to moderate. Serious adverse events occurred in less than 0.1% of patients (bronchospasm, gastroenteritis, headache with hypertension, vaginal hemorrhage, and injection site pain or impaired movement). In overall safety evaluation, 10 vaccine and 7 placebo recipients died during the course of the trials; none of the deaths was considered to be vaccine related.6Markowitz LE Dunne EF Saraiya M Lawson HW Chesson H Unger ER Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56 (Accessed Apr 28, 2008.): 1-24http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htmPubMed Google Scholar, 19Gardasil [human papillomavirus quadrivalent (types 6,11,16,18) vaccine, Recombinant] [package insert]. Merck & Co, Whitehouse Station, NJ2006http://www.fda.gov/cber/label/gardasilLB.pdfGoogle Scholar The HPV vaccine is currently not licensed for use in female patients younger than 9 years or older than 26 years or for use in male patients. It is contraindicated in people with history of immediate hypersensitivity to yeast or to any vaccine component. The vaccine should be deferred in patients with moderate or severe acute illnesses. Patients should be observed for syncope for 15 minutes after vaccine administration. The vaccine is also not recommended for use in pregnant women. Although it has not been causally associated with adverse outcomes of pregnancy, data are limited. The vaccine is classified as Category B on the basis of animal studies in rats showing no evidence of impaired fertility or harm to the fetus. Any exposure to the vaccine during pregnancy must be reported to the vaccine pregnancy registry (1-800-986-8999). Lactating women can receive the HPV vaccine. Immunosuppressed female patients can receive the vaccine, but its efficacy and the degree of immune response it elicits could be poorer in this population.19Gardasil [human papillomavirus quadrivalent (types 6,11,16,18) vaccine, Recombinant] [package insert]. Merck & Co, Whitehouse Station, NJ2006http://www.fda.gov/cber/label/gardasilLB.pdfGoogle Scholar The prevention and treatment of anogenital warts and cervical HPV-related disease imposes an estimated burden of more than $4 billion (2004 dollars) in direct costs in the United States each year, with $200 million attributable to management of genital warts, $300 to $400 million to treatment of invasive cervical cancer, and the remainder to routine cervical cancer screening, follow-up of abnormal Pap tests, and preinvasive cervical cancer. These figures do not include the costs of other HPV-related diseases (eg, vaginal and anal cancers, RRP). Markov models have suggested that vaccination of an entire cohort of female patients aged 12 years could significantly reduce lifetime risk of cervical cancer, as well as decrease Pap test abnormalities and cervical cancer precursor lesions. Models that incorporate HPV transmission dynamics suggest that vaccination could have an even greater effect. Since 2003, 4 studies have estimated the potential cost-effectiveness of routine HPV vaccination of female patients aged 12 years to range from $3000 to $24,300 per quality-adjusted life-year (QALY).6Markowitz LE Dunne EF Saraiya M Lawson HW Chesson H Unger ER Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56 (Accessed Apr 28, 2008.): 1-24http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htmPubMed Google Scholar For example, one of the Markov model studies assumes 100% vaccine coverage with 90% vaccine efficacy against HPV-16 and HPV-18 and lifetime duration of protection at a cost of $377 per vaccine series; under these assumptions, an estimated 58% reduction in lifetime risk of cervical cancer for the vaccinated cohort would be achieved at a cost of $24,300 (2002 dollars) per QALY compared with no vaccination. Dynamic transmission models incorporating benefits of vaccination on HPV transmission in the population (herd immunity) can be used with varying assumptions. If one assumes inoculation at age 12 years with a targeted HPV-16 and HPV-18 vaccine ($300 per series) with 90% efficacy and 10-year duration of protection plus 10 additional years with a booster dose ($100 per booster), lifetime risk for cervical cancer among vaccinated female patients would be reduced by 62% at a cost per QALY of $14,600 (2001 dollars). A 75% reduction in cervical cancer at a cost of $3000 per QALY (in 2005 dollars) would be projected if one assumed inoculation at age 12 years or younger with an HPV-6/11/16/18 vaccine (average cost, $360 per series) that has 90% efficacy against infection and 100% efficacy against HPV-related diseases attributable to the targeted HPV types with lifelong duration of protection and 70% vaccine coverage.6Markowitz LE Dunne EF Saraiya M Lawson HW Chesson H Unger ER Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56 (Accessed Apr 28, 2008.): 1-24http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htmPubMed Google Scholar The current market price of $360 for the vaccine series does fall within the range estimates used in these models; however, cost of vaccine administration, including physician's visits, increases actual cost. The Advisory Committee on Immunization Practices currently recommends routine vaccination of female patients aged 11 to 12 years with 3 doses of the quadrivalent HPV vaccine. Vaccination can be given to female patients as young as 9 years, as well as to female patients aged 13 to 26 years who have not previously completed vaccination. Pap testing and screening for HPV DNA or HPV antibody before vaccination is not needed. Routine cervical cancer screening should be continued.6Markowitz LE Dunne EF Saraiya M Lawson HW Chesson H Unger ER Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56 (Accessed Apr 28, 2008.): 1-24http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htmPubMed Google Scholar The American College of Obstetricians and Gynecologists recommends that HPV vaccination be offered to all female patients aged 9 to 26 years who have not been previously vaccinated and also emphasizes continued regular cervical cytology screening.20American College of Obstetricians and Gynecologists HPV Vaccine—ACOG Recommendations.http://www.acog.org/departments/dept_notice.cfm?recno=7&bulletin=3945Google Scholar In contrast, the American Cancer Society does not consider existing evidence to be sufficient to recommend or warn against routine vaccination for women older than 18 years. Because women aged 19 to 26 years are more likely to have been exposed already to HPV, the American Cancer Society suggests that the decision to vaccinate women in this age range should be made on an individual basis.4Saslow D Castle PE Cox JT Gynecologic Cancer Advisory Group et al.American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors.CA Cancer J Clin. 2007; 57: 7-28Crossref PubMed Scopus (444) Google Scholar Three months after the Food and Drug Administration licensed Merck's HPV vaccine, Michigan lawmakers began proposing that vaccination be compulsory for girls entering the sixth grade. In February 2007, Texas became the first state to mandate it; however, this order was later overridden. At least 24 states and the District of Columbia have introduced legislation to specifically mandate the HPV vaccine for school.21National Conference of State Legislatures HPV vaccine legislation 2007-2008.http://www.ncsl.org/programs/health/HPVvaccine.htmGoogle Scholar Opponents of mandatory inoculation include antivaccine activists who argue that the vaccine has not been sufficiently tested in young girls, conservative Christian groups who oppose mandatory HPV vaccinations on moral grounds, and those generally distrustful of the pharmaceutical industry.22Colgrove J The ethics and politics of compulsory HPV vaccination.N Engl J Med. 2006; 355: 2389-2391Crossref PubMed Scopus (139) Google Scholar More research is needed regarding duration of protective immunity and need for booster, further monitoring for HPV-associated lesions, effect on prevalence and incidence of HPV types included in the vaccine, general safety and pregnancy outcomes, safety and immunogenicity of simultaneous administration with other vaccines, efficacy in female patients older than 26 years and in male patients, effect on cervical cancer screening practices and on safe sex behavior, and further economic analysis. A bivalent vaccine directed against HPV-16 and HPV-18 by GlaxoSmithKline is expected to be on the market some time in 2008. Also administered in 3 doses (at 0, 1, and 6 months), it has been reported to be highly immunogenic and safe.23Harper DM Franco EL Wheeler CM HPV Vaccine Study Group et al.Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial.Lancet. 2006; 367: 1247-1255Abstract Full Text Full Text PDF PubMed Scopus (1413) Google Scholar, 24Paavaonen J Jenkins D Bosch F HPV PATRICIA Study Group et al.Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial.Lancet. 2007; 369: 2161-2170Abstract Full Text Full Text PDF PubMed Scopus (1130) Google Scholar Head-to-head trials are reportedly planned. Human papillomavirus infection is the most common sexually transmitted infection in the United States. Persistent infection with high-risk types can lead to precancerous and cancerous lesions. The new quadrivalent HPV vaccine appears to confer a high degree of protection against HPV-6, HPV-11, HPV-16, and HPV-18, which are responsible for 70% of cervical cancers and 90% of genital warts. If the vaccine's duration of protection proves to be sufficient or can be maintained through booster vaccinations at cost-effective levels, we can anticipate promising results with population-wide vaccination.