March 01, 2010
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Clinical Controversies and Challenges in HPV Vaccination

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Clinical Controversies and Challenges in HPV Vaccination

Introduction

HPV Vaccination: Understanding and Applying the Recommendations Kenneth A. Alexander, MD, PhD

HPV Immunization in Males
Kenneth A. Alexander, MD, PhD

HPV Vaccination and Pre-teens: Strategies to Improve Immunization Rates
Amanda Frisch Dempsey, MD, PhD, MPH

Discussion


Introduction

Human papillomaviruses (HPVs) are associated with a significant disease burden. In addition to genital warts, HPVs are responsible for virtually all cases of cervical cancer, which is estimated to affect 500,000 women each year. HPVs are also associated with other anogenital cancers and head and neck cancers. Moreover, there has been an evolution in thought from the belief that HPVs cause disease only in women to the realization that HPVs are associated with a significant disease burden in men as well.

A quadrivalent HPV vaccine has been available since 2006. This vaccine protects against HPV types 6, 11, 16, and 18. A bivalent vaccine protecting against types 16 and 18 also became available recently. Both vaccines are indicated for females and the Food and Drug Administration (FDA) recently expanded the indication of the quadrivalent vaccine to include males. Both vaccines have been shown to be highly efficacious in preventing precancerous cervical lesions and the quadrivalent vaccine has been effective in preventing genital warts. Both vaccines are associated with only minor adverse events. Despite the proven efficacy and safety of these vaccines, immunization rates are low.

Vindico Medical Education conducted a live program held during the 22nd annual Infectious Diseases in Children symposium in New York in November 2009 to review the HPV vaccines and to provide updates regarding the FDA indications and the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices’ recommendations regarding HPV immunization. The rationale for immunizing males against HPV was also discussed. Importantly, controversies surrounding HPV vaccination and barriers to achieving optimal immunization rates were presented along with strategies to overcome these obstacles. This monograph summarizes the presentations and discussions that took place during this program.

I thank Amanda Frisch Dempsey, MD, PhD, MPH, for her contributions to the presentation and discussions that led to the development of this monograph, from which readers can expect to receive an update on HPV immunization and advice on how to implement vaccination in their practices.

Kenneth A. Alexander, MD, PhD
Course Chair

Kenneth A. Alexander, MD, PhD Kenneth A. Alexander, MD, PhD
Course Chair
Associate Professor of Pediatrics
Chief, Pediatric Infectious Diseases
University of Chicago
Chicago, IL
Amanda Frisch Dempsey, MD, PhD, MPH Amanda Frisch Dempsey, MD, PhD, MPH
Assistant Professor
Department of Pediatrics and Communicable Diseases
University of Michigan
Ann Arbor, MI

HPV Vaccination: Understanding and Applying the Recommendations

Kenneth A. Alexander, MD, PhD

Human papillomaviruses (HPVs) are double-stranded DNA viruses that are transmitted through sexual contact and are detectable in nearly 100% of cervical cancer cases. 1 More than 200 genotypes of HPV have been identified. 1 High-risk genotypes (ie, types 16, 18, 31, 33, and 45) of HPV are associated with low-grade cervical changes, high-grade cervical changes, cervical cancer, and other anogenital cancers. 2,3 Low-risk genotypes (eg, types 6 and 11) are associated with benign or low-grade cervical changes and condyloma acuminata (genital warts).1,4 Studies of the natural history of HPV infection have revealed that the pathology of the disease also extends beyond the cervix and anogenital area. For example, certain high-risk types of HPV have been shown to be associated with head and neck cancer and low-risk types have been shown to be associated with recurrent respiratory papillomatosis (RRP). 4,5

The burden of HPV-related disease is significant. In the United States, approximately 10 000 cases of cervical cancer and another 7000 cases of malignancies in related sites are diagnosed annually. In addition, there are millions of women with abnormal Pap tests that must be followed and managed to ensure they do not progress to cervical cancer. Types 16 and 18 together account for 70% of high-grade cervical malignancies; types 6 and 11 account for approximately 90% of cases of genital warts and a large proportion of low-grade neoplasias. There is also a significant burden of malignant disease associated with HPV in males. An estimated 7500 cases of HPV-associated malignancies occur in males each year and there is speculation that the incidence of oropharyngeal and oral cancers may be underestimated in this population. 6,7

Two HPV vaccines, each targeting high-risk genotypes, are available and have been shown to be highly efficacious for prevention of HPV-associated malignancies in females. An understanding of the compositions of the 2 available vaccines and the recommendations of the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) regarding administration of the vaccines is critical for reducing the burden of HPV-related disease.

Quadrivalent HPV Vaccine

Composition

The first HPV vaccine to become available was the quadrivalent HPV-6/11/16/18 vaccine (Gardasil, Merck and Co., Inc), which was approved by the US Food and Drug Administration (FDA) in 2006. This is a pseudovirion- based vaccine, composed of noninfectious, recombinant, virus-like particles (VLPs). 8 The VLPs are produced by the expression of the L1 protein (the major capsid protein of the virus) in yeast cells. The expressed L1 proteins subsequently self-assemble into icosohedral structures that are identical to the naturally occurring viral capsid. Because these structures are assembled without viral DNA, the VLPs are noninfectious. VLPs have been shown to elicit strong systemic immune responses. The quadrivalent vaccine comprises VLPs of HPV types 6, 11, 16, and 18, and contains a proprietary adjuvant of aluminum hydroxyphosphate sulfate. The quadrivalent vaccine is administered intramuscularly as three 0.5-mL doses with second and third doses administered 2 and 6 months after the first dose in the series, respectively.

Efficacy and safety

The efficacy and safety of the quadrivalent vaccine have been studied extensively. 8,9 The quadrivalent HPV vaccine is more than 95% efficacious in the prevention of cervical, vulvar, and vaginal dysplasias, genital warts, and malignancies due to vaccine HPV types (Table 1). No major vaccine-related adverse events have been identified. The minor adverse events associated with the vaccine are primarily injection-site related.

ACIP recommendations for females (Male HPV vaccination is discussed on page 9)

The ACIP recommends routine vaccination of females aged 11–12 years with 3 doses of the quadrivalent HPV vaccine. Vaccination is also recommended for females aged 13–26 years who have not been vaccinated or who have not completed the full series. 10 The ACIP also states that the vaccine may be given to females as young as 9 years of age.

Bivalent HPV Vaccine

A bivalent HPV vaccine (Cervarix, GlaxoSmithKline) was approved by the FDA in 2009. The bivalent vaccine is also pseudovirion-based and contains VLPs of HPV types 16 and 18. This vaccine is the first commercially available vaccine to be prepared in insect cell culture; the VLPs were produced by infecting the Spodoptera frugiperda (SF9) insect cell line with recombinant baculoviruses that encode the L1 capsid protein. The bivalent vaccine contains a novel proprietary adjuvant, aluminum hydroxide with 3-deacylated monophosphoryl lipid A (ASO4). The bivalent vaccine also follows a 3-dose administration schedule and is administered at 0, 1, and 6 months. Like the quadrivalent vaccine, the bivalent vaccine has an efficacy in excess of 95% for the prevention of cervical dysplasias and malignancies due to vaccine HPV types (Table 2). 8,11 This vaccine is also well tolerated. The ACIP recommends that the bivalent vaccine be administered to females aged 11–12 years, with vaccination allowed as young as age 10, with catch-up vaccination for women between the ages of 13 and 25 years who have not previously been vaccinated.12 This vaccine does not provide protection against genital warts.

HPV Vaccine Indications

The bivalent vaccine is indicated for the prevention of HPV-16 and HPV-18 infections, and for the prevention of cervical intraepithelial neoplasia grade 1 (CIN1), CIN2, and CIN3 (Table 3). 13 The quadrivalent vaccine has similar indications, but its indications are extended to the prevention of vaginal and vulvar neoplasia, genital warts in females and, recently, to the prevention of genital warts in males (Table 3). 14 The bivalent vaccine is indicated for females aged 10–25 years; the quadrivalent vaccine is indicated for females and males aged 9–26 years. 13,14

Controversies Surrounding HPV Immunization

Unfortunately, HPV immunization rates among adolescents and pre-teens remain low. Teen data from the CDC’s National Immunization Study indicate that, in 2008, only 37.2% of adolescent females had initiated the HPV vaccination series (1 dose), and only 18% received all 3 doses. 15 There are a number of possible reasons for these suboptimal HPV immunization rates.

HPV vaccine safety concerns

Despite the exceptional safety profile of the HPV vaccines, safety concerns have emerged. For example, following FDA approval of the vaccine, fainting was observed among adolescent females, 16 which was unanticipated, as fainting was not observed in prelicensure trials within 20 minutes of vaccination. During vaccine clinical trials, the participants remain seated for a period of observation. Ultimately, the FDA concluded that the fainting episodes were due to the vaccination process and not to the vaccine, as fainting episodes have occurred following immunization with other vaccines as well. 17 To prevent fainting of vaccinees, physicians are encouraged to have their adolescent and young adult patients remain seated in the exam room or waiting room for 15–20 minutes after receiving any vaccine. 18

Table 1. Analysis of Efficacy of the Quadrivalent Human Papillomavirus (HPV) Vaccine in Females Aged 16–26 Years Naïve to HPV Vaccine Types
Table 1. Analysis of Efficacy of the Quadrivalent Human Papillomavirus (HPV) Vaccine in Females Aged 16–26 Years Naïve to HPV Vaccine Types
Key: AAHS—amorphous aluminum hydroxyphosphate sulfate; AIS—adenocarcinoma in situ; CIN—cervical intraepithelial neoplasia; VaIN—vaginal intraepithelial neoplasia. VIN—vulvar intraepithelial neoplasia.Source: Gardasil Prescribing Information. Available at: http://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf. Accessed January 12, 2010.


Click here for larger version of Table 1.

HPV vaccine safety concerns have also risen from media reports describing tragic events, such as seizures, paralysis, and sudden death of teenaged girls following administration of the HPV vaccine. While extensive vaccine safety surveillance has revealed no causal link between HPV vaccine administration and these events, some in the lay press, as well as many immunization critics, continue to advocate against HPV immunization, branding the vaccine as unsafe.

A possible explanation for these fears is the misuse, misinterpretation, and improper citing of data from the Vaccine Adverse Event Reporting System (VAERS). VAERS is a national passive reporting system available to anyone who would like to report a potential vaccine- related adverse event. 19 This broad acceptance allows for high sensitivity in the detection of adverse events; however, like any very sensitive detection method, nonspecific results are also obtained. In the case of VAERS, posted reports are not screened, and no cause and effect relationship between immunization and adverse events can be inferred. 19 On occasion, multiple reports of the same adverse event are also filed, thereby skewing the reported data. Moreover, as VAERS reports can be seen by everyone, individuals unfamiliar with the proper use of the system may misread the reports and draw inaccurate conclusions from them. VAERS is a passive reporting system; it cannot be used to calculate incidence rates. VAERS data can be used to generate a hypothesis but cannot be used to test a hypothesis, since VAERS data lack a denominator. 19 Any hypothesis created from VAERS data must be tested through controlled trials. For example, VAERS resulted in the initial detection of a possible association of intussusception with the first-generation rotavirus vaccine. After reviewing VAERS data, investigators formed a hypothesis and designed studies that ultimately led to the voluntary withdrawal of this vaccine from the market. 20

The CDC Vaccine Safety Data Link (VSD) system can be used to test a hypothesis generated through interpretation of VAERS data. VSD is a large collaborative of healthcare organizations that is used to prospectively study potential immunization-related adverse events. 21 Specific protocols are set up prospectively. Because the exact number of patients enrolled is known, there is a denominator for each studied event. Examination of VSD-generated data led the FDA to conclude that the type and frequency of adverse events reported for the quadrivalent HPV vaccine were consistent with the type and frequency of events expected in healthy populations. Restated, given a population of 15 million people (the approximate number of people who have been immunized against HPV), a certain proportion would experience events such as seizures, paralysis, and sudden death regardless of whether they have received a vaccine.

Table 2. Efficacy of Bivalent Human Papillomavirus (HPV) Vaccine Against Diseases Associated with HPV-16 or HPV-18 in Females Aged 15–25 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types
Table 2. Efficacy of Bivalent Human Papillomavirus (HPV) Vaccine Against Diseases Associated with HPV-16 or HPV-18 in Females Aged 15–25 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types
Key: AIS—adenocarcinoma in situ; CIN—cervical intraepithelial neoplasia.Source: Cervarix Prescribing Information. Available at: http://us.gsk.com/products/assets/us_cervarix.pdf. Accessed January 12, 2010.


Click here for larger version of Table 2.

Morality issues surrounding HPV immunization

Morality concerns have complicated the process of HPV immunization. For example, Bridget Maher of the Family Research Council, an organization initially opposed to HPV immunization, stated that “giving the HPV vaccine to young women could be potentially harmful because they may see it as a license to engage in premarital sex.”22 Moreover, some parents feel that 11–12 years of age is too young to receive the HPV vaccine because their child is not going to be sexually active at that age.

Endpoints in HPV Vaccine Clinical Trials

An important issue surrounding the evaluation of HPV vaccines is the determination of which study endpoints should be used in clinical trials. For HPV vaccine efficacy study endpoints, there are a variety of options, each with its own advantages and disadvantages. Cervical cytology is a reasonable study endpoint to use, since the goal of HPV immunization is to prevent CIN1, CIN2, and CIN3, as well as cervical cancer. The challenge, however, is that many people have mixed infections, causing a problem of attribution to arise. In cases of mixed infection, which of the 2 strains is causing the observed abnormalities is not known, and in fact both strains could be contributing to the cytological abnormalities. This issue is difficult to resolve. Furthermore, the correlation between cytology and molecular virology is not perfect.

Another option is to use persistent infection as an endpoint. One of the surrogate markers for the risk of cervical cancer is the development of a persistent HPV infection. 23 In other words, if someone is infected with HPV and ultimately clears the infection clinically, the likelihood of that individual developing cancer from that HPV type is very low. On the other hand, if the infection persists, there is an increased risk for malignancy. Thus, the efficacy of HPV vaccines in preventing persistent infection portends efficacy in preventing HPV-related cancers. Another advantage of using persistent infection as an endpoint is that persistent infection has a measurable start and finish, from virus detection to when the infection is cleared. Moreover, persistent infection can be assessed for each individual HPV type, which alleviates the problem of attribution in cases of mixed infection.

One of the surrogate markers for the risk of cervical cancer is the development of a persistent HPV infection.
— Kenneth A. Alexander, MD, PhD

Because incident infection is not generally believed to be associated with cervical cancer risk, prevention of incident infection is not a reasonable endpoint to use when investigating the efficacy of HPV vaccines in the prevention of cervical cancers.

HPV Vaccine Cross-Protection

HPV vaccine cross-protection against non-vaccine oncogenic strains is expected to occur for a variety of reasons. First, the vaccines are highly immunogenic. Also, the pseudovirions that comprise HPV vaccines are based on the L1 capsid protein, the amino acid sequence of which is the basis for defining HPV type, and there is substantial conservation within the L1 structures among HPV vaccine types. 24

There are 4 published studies examining cross-protection of HPV. 25–28 Comparing the results of these studies is difficult, as the studies differ in methodology, endpoints, populations, and the vaccine under investigation. However, with these caveats in mind, limited comparisons can be made and a few conclusions can be drawn from these studies. Using prevention of 6-month persistent infection as an endpoint, the quadrivalent vaccine was observed to have significant cross-protection against HPV-31. 27,28 The bivalent vaccine was observed to have significant efficacy against HPV-31, -45, and -52. 25,26 Analysis of data on prevention of persistent infection suggests that cross-protection may add between 2% and 5% increased protection against cervical cancers.

Overall, both vaccines exhibit cross-protection, but more work is needed to further characterize the cross-protection of the 2 vaccines. For example, the durability of cross-protection is not known. Cross-protection has not yet been studied in large populations. Importantly, the FDA has not licensed either vaccine for cross- protection. Thus, when physicians discuss cross-protection with patients, it must be made clear that it is an off-label use. Someday, broader protection may be achieved by adding antigens to the vaccines. A 9-valent vaccine is currently under investigation.

Adolescents are a vulnerable population, with increased risk of HPV infection and the eventual development of cervical malignancies. The licensed HPV vaccines are safe and effective. Both are recommended for administration to females aged 11–12 years with catch-up immunization also recommended. The quadrivalent vaccine is also recommended for use in males. Despite these recommendations, HPV immunization rates are suboptimal, perhaps due to safety-related misperceptions and moral concerns related to vaccination. Strategies to overcome barriers to immunization are discussed later in this monograph.

Table 3. FDA-approved Indications for Human Papillomavirus (HPV) Vaccine
Table 3. FDA-approved Indications for Human Papillomavirus (HPV) Vaccine
Sources: FDA-approved Indications for Gardasil. Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM094042. Accessed January 15, 2010; FDA-approved Indications for Cervarix. Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM094042. Accessed January 15, 2010.


Click here for larger version of Table 3.

References

  1. Castellsagué X. Natural history and epidemiology of HPV infection and cervical cancer. Gynecol Oncol. 2008;110:S4-S7.
  2. Koutsky LA, Galloway DA, Holmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev. 1988;10:122–163.
  3. Muñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–527.
  4. Hansson BG, Rosenquist K, Antonsson A, et al. Strong association between infection with human papillomavirus and oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. Acta Otolaryngol. 2005;125:1337–1344.
  5. Wiatrak BJ. Overview of recurrent respiratory papillomatosis. Curr Opin Otolaryngol Head Neck Surg. 2003;11:433–441.
  6. Watson M, Saraiya M, Ahmed F, et al. Using population-based cancer registry data to assess the burden of human papillomavirus-associated cancers in the United States: overview of methods. Cancer. 2008;113:2841–2854.
  7. Watson M, Saraiya M, Benard V, et al. Burden of cervical cancer in the United States, 1998-2003. Cancer. 2008;113:2855–2864.
  8. Cutts FT, Franceschi S, Goldie S, et al. Human papillomavirus and HPV vaccines: a review. Bull World Health Organ. 2007;85:719–726.
  9. Gardasil Prescribing Information. Available at: http://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf. Accessed January 12, 2010.
  10. CDC. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2007;56(RR-2):1–24.
  11. Cervarix Prescribing Information. Available at: http://us.gsk.com/products/assets/us_cervarix.pdf. Accessed January 12, 2010.
  12. CDC Panel Recommends HPV Vaccine Cervarix for Girls, Optional Gardasil Vaccination for Boys. Available at: http://www.medicalnewstoday.com/articles/168449.php. Accessed January 8, 2010.
  13. DA-approved Indications for Cervarix. Available at: http://knol.google.com/k/cervarix-glaxo-smith-kline-vaccine-for-cervical-cancer#. Accessed January 10, 2010.
  14. FFDA-approved Indications for Gardasil. Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM094042. Accessed January 12, 2010.
  15. CDC. National, state, and local area vaccination coverage among adolescents aged 13-17 years-United States, 2008. CDC. MMWR. 2009;58:997–1001.
  16. Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA. 2009;302:750–757.
  17. CDC. Syncope after vaccination–United States, January 2005-July 2007. MMWR.2008;57:457-460.
  18. Kroger AT, Atkinson WL, Marcuse EK, Pickering LK; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR. 2006;55(RR-15):1–48.
  19. CDC. Vaccine Adverse Event Reporting System (VAERS). Available at: http://vaers.hhs.gov/index/about/index. Accessed February 24, 2010.
  20. CDC. Intussusception among recipients of rotavirus vaccine–United States, 1998-1999. MMWR. 1999;48:527–581.
  21. CDC. Vaccine Safety Datalink (VSD) Project. Available at: http://www.cdc.gov/vaccinesafety/Activities/vsd.html. Accessed Janury 12, 2010.
  22. Family Research Council opposes vaccine that could stop spread of HPV. Available at: http://www.thefreelibrary.com/Family+Research+Council+opposes+vaccine+that+could+stop+spread+of+HPV-a0134625957. Accessed January 12, 2010.
  23. Nobbenhuis MA, Walboomers JM, Helmerhorst TJ, et al. Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening: a prospective study. Lancet.1999;354:20–25.
  24. Bishop B, Dasgupta J, Klein M, et al. Crystal structures of four types of human papillomavirus L1 capsid proteins: understanding the specificity of neutralizing monoclonal antibodies. J Biol Chem. 2007;282:31803–31811.
  25. Harper DM, Franco EL, Wheeler CM, 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;367:1247–1255.
  26. Paavonen J, Jenkins D, Bosch FX, 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;369:2161–2170.
  27. Brown DR, Kjaer SK, Sigurdsson K, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16-26 years. J Infect Dis. 2009;199:926–935.
  28. Wheeler CM, Kjaer SK, Sigurdsson K, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16-26 years. J Infect Dis. 2009;199:936–944.

HPV Immunization in Males

Kenneth A. Alexander, MD, PhD

Human papillomavirus (HPV) infections are common in males as they are in females. In a study of 463 men aged 18–40 years without a history of genital warts, 51.2% tested positive for HPV. 1 Up to 72.9% of men have acquired genital HPV infection. HPV infection is associated with a variety of diseases in males, including genital warts, anal dysplasias/cancers, penile cancers, oropharyngeal/oral cavity cancers, and recurrent respiratory papillomatosis. Given the burden of HPV-associated disease in males, HPV vaccination of males merits consideration.

HPV-Associated External Genital Lesions in Males

HPV-associated genital lesions are a significant burden in males as well as females. Approximately 500,000 cases of genital warts occur in males each year, which results in more than $200 million in health care costs. 2,3 Genital warts recur frequently, and can persist for a lifetime. The diagnosis of genital warts is often associated with a significant reduction in quality of life. 4

HPV Vaccine Efficacy in Males

The efficacy of the quadrivalent HPV vaccine for the prevention of genital lesions in males was investigated in a randomized, double-blind, placebo-controlled trial. The trial included 3463 heterosexual men (HM) aged 16–23 years and 602 men who have sex with men (MSM) aged 16–26 years, from multiple countries/continents. All participants were without a history of possible HPV-related genital warts and lesions and all had 1–5 lifetime sexual partners. Results of this study demonstrated that the vaccine was approximately 90% efficacious in the prevention of external genital lesions and condyloma related to HPV-6, -11, -16, or -18 in males (Table 1). 5,6

Table 1. Quadrivalent HPV Vaccine Efficacy in Males
Table 1. Quadrivalent HPV Vaccine Efficacy in Males
Key: AAHS—amorphous aluminum hydroxyphosphate sulfate; PIN—penile intraepithelial neoplasia.Sources: Palefsky J, et al. Efficacy of the quadrivalent HPV vaccine against HPV 6/11/16/18-related genital infection in young men. EUROGIN. Nice, France, November 12–15, 2008. PS 1-3a. Available at: www.eurogin.com/2008/EUROGIN2008_LastMinuteAbstracts.pdf. Accessed January 20, 2010; Giuliano AR, et al. The efficacy of quadrivalent HPV (types 6/11/16/18) vaccine in reducing the incidence of HPV-related genital disease in young men. EUROGIN. Nice, France, November 12–15, 2008. SS 19-7a. Available at: www.eurogin.com/2008/EUROGIN2008_LastMinuteAbstracts.pdf. Accessed January 20, 2010.


Click here for larger version of Table 1.

The data from this clinical trial prompted the Food and Drug Administration (FDA) to expand the indications for the quadrivalent vaccine to include the prevention of genital warts in males aged 9–26 years. 7 Moreover, the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) recently released a permissive recommendation that the quadrivalent vaccine be administered to males aged 9–26 years for the prevention of external genital lesions. 8

A permissive recommendation differs from an affirmative recommendation in that ACIP is not stating that the vaccine must be given; rather, ACIP is stating that administering the vaccine may be beneficial. With a permissive recommendation, providers may offer the vaccine but immunizers are not expected to offer the vaccine proactively, as they are with an affirmative recommendation. Vaccine uptake is not a measure of provider performance, as it is with an affirmative recommendation. The vaccine is still available through the Vaccines for Children Program (VFC). If a VFC-eligibile patient requests the vaccine, providers are required to administer the vaccine, as they are with an affirmative recommendation. If they do not have the vaccine in stock, they must refer the patient to a physician who does.

Other Reasons for Protecting Males against HPV

In addition to protecting against HPV-associated genital warts, other motives for administering the HPV vaccine to males merit consideration. For example, immunizing males against HPV could conceivably reduce the risk of male-to-female transmission, thereby reducing the incidence of cervical cancer and other manifestations of HPV-related diseases in females. However, more research is required to prove this hypothesis.

HPV and Cancer in Males

There is a theoretical basis for administering the HPV vaccine to protect males against head and neck and anal malignancies. Recently, it has been recognized that a significant and increasing proportion of oropharyngeal carcinomas is attributable to HPV (predominantly HPV-16). 9

The burden of HPV in males approximates the burden in females.
— Kenneth A. Alexander, MD, PhD

For example, the incidence of base of tongue cancer as well as the proportion of HPV-positive tumors has increased in Sweden. 10 The overall incidence of base of tongue cancer increased from 0.15/100,000 person- years during 1970–1974 to 0.47/100,000 person-years during 2000–2005 in Sweden. The prevalence of HPV in base of tongue cancer in Stockholm county increased from 58% during 1998–2001 to 84% during 2004–2007. 10

Similarly, the incidence of anal cancers is increasing in both males and females. Between 1973 and 2003, there was a 2-fold increase in anal malignancies in males. 11 There are an estimated 2020 new anal cancers annually. Of these, 1818 have been attributed to HPV (Table 2). 12–15

When the estimated numbers of HPV-related oral/ oropharyngeal, laryngeal, anal/rectal, and penile malignancies are added, the sum roughly equals the 11,000 cases of cervical malignancies that occur each year (Table 2). Thus, the burden of HPV-associated malignancies in males approximates the burden in females.

Table 2. Annual Number of New Cases of HPV-Related Cancers in US Men
Table 2. Annual Number of New Cases of HPV-Related Cancers in US Men
Sources: American Cancer Society. Cancer facts & figures 2008. Available at: http://www.cancer.org/acs/groups/content/@nho/documents/document/2008cafffinalsecuredpdf.pdf. Accessed February 22, 2010; Kreimer AR, et al. Cancer Epidemiol Biomakers Prev. 2005;14:467–475; Ryan DP, et al. N Engl J Med. 2000;342:792–800; Daling JR, et al. Int J Cancer. 2005; 116:606–616


Click here for larger version of Table 2.

Unfortunately, the burden of HPV-associated diseases in males is high and, while there are substantial data indicating that HPV vaccines should be effective for prevention of head and neck malignancies, no clinical trials to determine HPV vaccine efficacy for prevention of head and neck malignancies have been performed, nor should such a trial be anticipated in the near future. A trial to assess the efficacy of HPV vaccination for prevention of head and neck malignancies would be difficult and lengthy because, unlike cervical and anal cancers, which have well-established pre-cancerous conditions (eg, cervical intraepithelial neoplasia grade 2, cervical intraepithelial neoplasia grade 3, and anal intraepithelial neoplasia, respectively), no such pre-cancerous conditions have been identified for head and neck malignancies; malignancy would be the sole study endpoint. Thus, a vaccine efficacy trial would take decades to complete.

Cost-benefit Analyses of HPV Immunization

While there is substantial medical evidence supporting immunization of males against HPV, the cost-benefit of male immunization must also be assessed. Cost-effectiveness of vaccinating females against HPV is well established. Cost-benefit analysis of HPV immunization of males depends upon a variety of factors, including female immunization rates, the disease(s) in question (warts, cancer, etc), vaccine cost, vaccine efficacy, and age at immunization.

Cost-benefit analysis of HPV immunization of males indicates that cost-benefit improves as the number of measured outcomes for male immunization increases. For example, immunizing males for the purpose of protecting against cervical outcomes and genital warts is more cost-effective than protecting against only cervical outcomes in females. Immunizing males to protect against cervical outcomes, genital warts, non-cervical cancers, and juvenile-onset recurrent respiratory papillomatosis is even more cost-effective. Not surprisingly, as female immunization rates increase, male immunization becomes less cost-beneficial.

The cost-benefit of immunizing males against HPV improves as the number of measured outcomes for male immunization increases.
— Kenneth A. Alexander, MD, PhD

In summary, HPV is as significant a burden in males as it is in females. Recent studies have demonstrated that the quadrivalent HPV vaccine is highly effective for the prevention of genital warts in males. On the basis of this finding, the FDA has expanded the indications for the quadrivalent vaccine to include the prevention of genital warts in males aged 9–26 years. Furthermore, the ACIP has given a permissive recommendation that the quadrivalent HPV vaccine be administered to males in this age group for the prevention of external genital lesions. However, in many aspects, the “unspoken” goal of HPV immunization of males is prevention of the more significant manifestation of HPV infection, HPV-associated cancers.

References

  1. Nielson CM, Flores R, Harris RB, et al. Human papillomavirus prevalence and type distribution in male anogenital sites and semen. Cancer Epidemiol Biomarkers Prev. 2007;16:1107–1114.
  2. Hoy T, Singhal PK, Willey VJ, Insinga RP. Assessing incidence and economic burden of genital warts with data from a US commercially insured population. Curr Med Res Opin. 2009;25:2343–2351.
  3. Insinga RP, Dasbach EJ, Elbasha EH. Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature. Pharmacoeconomics. 2005;23:1107–1122.
  4. Woodhall S, Ramsey T, Cai C, et al. Estimation of the impact of genital warts on health-related quality of life.Sex Transm Infect. 2008;84:161–166.
  5. Palefsky J, Giuliano AR. Efficacy of the quadrivalent HPV vaccine against HPV 6/11/16/18-related genital infection in young men. EUROGIN. Nice, France, November 12-15, 2008. Available at: www.eurogin.com/2008/EUROGIN2008_LastMinuteAbstracts.pdf. Accessed April 22, 2010.
  6. Giuliano AR, Palefsky J. The efficacy of quadrivalent HPV (types 6/11/16/18) vaccine in reducing the incidence of HPV-related genital disease in young men. EUROGIN. Nice, France, November 12-15, 2008. Available at: www.eurogin.com/2008/EUROGIN2008_LastMinuteAbstracts.pdf. Accessed April 22, 2010.
  7. FDA-approved Indications for Gardasil. Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM094042. Accessed January 12, 2010.
  8. CDC Panel Recommends HPV Vaccine Cervarix For Girls, Optional Gardasil Vaccination For Boys. Available at: http://www.medicalnewstoday.com/articles/168449.php. Accessed January 8, 2010
  9. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26:612–619.
  10. Attner P, Du J, Näsman A, Hammarstedt L, et al. The role of human papillomavirus in the increased incidence of base of tongue cancer.Int J Cancer. October 23 2009. [Epub ahead of print]
  11. Horner MJ, Ries LAG, Krapcho M, et al. Available at: http://seer.cancer.gov/csr/1975_2006/index.html. Accessed January 13, 2010.
  12. American Cancer Society. Cancer facts & figures 2008. Available at: http://www.cancer.org/downloads/STT/2008CAFFfinalSecured.pdf. Accessed February 22, 2010.
  13. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14:467-475.
  14. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med. 2000;342:792-800.
  15. Daling JR, Madeleine MM, Johnson LG, et al. Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer. 2005;116:606-616.

HPV Vaccination and Pre-teens: Strategies to Improve Immunization Rates

Amanda Frisch Dempsey, MD, PhD, MPH

The Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) recommends routine immunization against human papillomavirus (HPV) for children 11–12 years of age. There are a variety of reasons to target this age group. However, overall immunization rates for these pre-teens are suboptimal. This is because there are various barriers to immunization of adolescents and pre-teens. Fortunately, there are strategies to overcome these barriers. Moreover, these strategies can be applied to other vaccines for this population, as there are challenges to providing vaccines to this age group that are not necessarily specific to HPV immunization.

Rationale for Targeting 11 to 12-Year-Olds for Immunization

There are both behavioral and biological reasons for administering the HPV vaccine to 11 to 12-year-olds. In terms of behavioral reasons, national data from 2007 indicated that 1 out of 14 children younger than 13 years of age engaged in penetrative vaginal intercourse. 1 By the age of 18 years, this number increased to 1 out of 2, 15% of whom had 4 or more partners.1 Determining which adolescent is going to become sexually active at such a young age is difficult. Therefore, it is critical to protect this vulnerable population as soon as possible.

Immunizing 11 to 12-year-olds against HPV is important from a biological perspective as well. The incidence of HPV infection is high among young women who become sexually active. For example, in a US study following a cohort of women aged 18–20 years who were virgins at the beginning of the study and then became sexually active during the study, it was found that approximately 30% became infected with HPV within 1 year and almost 40% became infected within 2 years (Figure 1). The minimum time between first sexual exposure and detection of HPV was less than 1 month. By the end of the study, which lasted approximately 4.5 years, the cumulative incidence of HPV infection had risen to 50% in this population. 2 Thus, HPV infection is common among young women who become sexually active, and risk of infection rises shortly after sexual debut (Figure 1). These results underscore the importance of immunizing patients before the onset of sexual activity.

Figure 1. Cumulative Incidence of HPV Infection
Figure 1. Cumulative Incidence of HPV Infection
In a cohort of females aged 18–20 years, the incidence of HPV was approximately 30% within 1 year of sexual debut and almost 40% within 2 years, emphasizing the importance of immunizing pre-teens before they become sexually active.
Source: Winer RL, et al. Am J Epidemiol. 2003;157:218–226, by permission of Oxford University Press.

Click here for larger version of Figure 1.

In their adolescent immunization schedule, ACIP has targeted 11 to 12-year-olds for a variety of other vaccines in addition to HPV. 3 There are biological reasons for targeting this age group for these vaccines as well. For example, when the rates of invasive meningococcal disease were examined, it was observed that although the highest rates of disease are in children younger than 1 year of age, there is a second peak in meningococcal disease that begins around the age of 12 years. 4 A similar pattern is observed with pertussis. Rates of pertussis infection decreased dramatically with the advent of the diphtheria, pertussis, and tetanus immunization. However, for children aged 11–18 years and individuals older than 19 years, a significant increase in pertussis cases was observed in the late 2000s.5 This increase is most likely due to waning immunity conferred from childhood immunization. Thus, it is critical that pre-teens receive these immunizations as well as the HPV vaccine.

Adolescent Immunization Rates

As stated earlier in this monograph, adolescent immunization rates are suboptimal despite the importance of immunizing this age group. Data released from the National Immunization Survey (NIS)-teen study in 2009 demonstrated that adolescent vaccination coverage was mixed. For vaccines typically administered during childhood, such as the varicella, measles-mumps-rubella (MMR), and hepatitis B vaccines, coverage was reasonably high, between 75% and 89%. 6 On the other hand, coverage was low for the adolescent vaccines: coverage for the meningococcal vaccine was only 42% 3 years after the vaccine was recommended, and Tdap coverage was only 41%. 6 Coverage for the HPV vaccine was 37% for the first dose and 18% for completion of the series. 6 Even though coverage had improved over the 2-year time span that these studies were conducted, all of the adolescent vaccines were below the Healthy People 2010 goal of 90%. 7

In another study investigating HPV immunization rates of adolescents and pre-teens, it was observed that the proportion of children aged 9–10 years that received the first dose of the vaccine was very low (Figure 2). 8

Furthermore, children aged 11–12 years were significantly less likely to initiate the HPV vaccine series than older adolescents ( P< .001, Figure 2). On the other hand, at least 70% of children who were eligible for second and third doses (ie, patients who received the prior vaccine dose and the recommended time interval between doses had passed) received them, and there were no statistically significant differences in completion of the 3-dose series once it had begun among the different age groups (Figure 2). 8 These results suggest that initiating the HPV vaccine series is a critical component in improving HPV immunization rates and may be a valid focus for future interventions for improvement of HPV vaccine coverage.

Figure 2. Initiation and Completion of the HPV Vaccine Series
Figure 2. Initiation and Completion of the HPV Vaccine Series
Coverage of the first dose was low among children aged 9–10 years, and coverage of children aged 11–12 years was significantly lower than older children. However, coverage of the second and third doses was over 70% of eligible children in all age groups, suggesting that series initiation may play a key role in improving HPV immunization rates.
Source: Dempsey A, et al. Vaccine. 2010;28:989–995.

Click here for larger version of Figure 2.

Assessing Immunization Rates in Your Practice

There are many methods by which immunization rates can be assessed in one’s practice. They vary by level of difficulty and ease of implementation. One of the most straightforward ways is to pull 100 charts of random adolescents in your practice and calculate the percentage that is up-to-date with their immunizations. This can be done by ancillary staff, such as a medical assistant or a nurse. This method can give a broad idea of how successful the practice is in terms of immunization in general and can also provide information about specific vaccines or age groups that are particularly problematic.

Another strategy for assessing immunization rates that requires slightly more effort is to contact the local or state health department for assistance. They may have a variety of tools for both implementing vaccines and assessing immunization rates of the practice. Moreover, health departments can provide regional or state level data that can be used to benchmark individual practices.

The gold standard for assessing immunization rates is AFIX (Assessment, Feedback, Incentives, and eXchange). 9 The assessment involves an automated program to determine how your practice is doing with immunization, and a variety of tools. Many states have immunization registries that allow for automatic assessment to be mined from those data sets. Alternatively, the Comprehensive Clinic Assessment Software Application (CoCASA) can be downloaded from the CDC Web site and used to assess immunization within your practice. This application can generate automated reports that can provide high level feedback about the immunization practices. Provider- specific information about specific vaccines or specific age groups can be received using this software. Once the feedback has been given, incentives are devised, and these can vary from monetary incentives to a pizza party for the office that has the best immunization coverage. A second assessment can later be performed to determine whether any of the strategies implemented may have helped to increase immunization rates. Throughout this process, exchange of information and ideas for helping to improve vaccine coverage occurs. Many health departments will carry out the AFIX process with or without CoCASA as a public service.

Barriers to Immunization

Barriers to adolescent immunization exist on multiple levels. Thinking of barriers in terms of those that are infrastructural and those related to people’s knowledge and attitudes can be helpful. In some cases, providers can create their own barriers to immunization.

Infrastructure barriers

One significant infrastructure barrier is the limited number of office visits by adolescents. This can be a major issue for health care providers who see a broad age range of patients or for those who practice in rural areas. In these circumstances, the clinician may have more pressing issues and not enough time to discuss vaccination with the adolescent. As a result, the clinician lacks experience with discussing the importance of immunization with this population. Moreover, adolescents in general tend to seek preventive health care such as well child check-ups less frequently than other child age groups. 10 This can lead to fragmented care and difficulty with record keeping.

Another infrastructure barrier is insurance concerns. Insurance plans vary considerably in terms of how they handle adolescent vaccine coverage. Some will cover vaccines up to age 21, some will cover up to age 16, and it can be difficult to know the specifics of each patient’s insurance plan.

There are a variety of ways to address infrastructure barriers.11 One strategy that has been shown to be effective is standing orders, which can be as simple as a piece of paper or an order sheet attached to the medical chart and checked by a nurse or a medical assistant to determine which vaccines are needed. The physician can review which vaccines were marked off as needed at the beginning of the visit and sign the order if they agree. Immunization- only appointments can also be effective. There is a standing order in the chart for a patient to come back to receive, for example, the second or third dose of the HPV vaccine. No physician interaction is necessary. The patient only interacts with the medical assistant. This lessens the time constraint on the patient to come into the office.

Reminder/recall systems that send notifications when a vaccine is due in the near future (reminder) or past-due (recall) are effective as well. Reminder/recall systems are built into many state immunization registries, and the health department can assist individual practices in finding out whether these are available for them to implement.

Other ways to address infrastructural barriers are using every visit as an opportunity for vaccination. This is where automated processes such as standing orders and reminder/recall systems can be helpful. Encouraging multiple vaccines at a single visit is also important. This means that providers must have accurate knowledge of the true contraindications to vaccination. For example, fever is not generally a contraindication for many vaccines, so if a child or adolescent visits your office with a fever, that can be an opportunity to vaccinate. To address insurance concerns, a practice can provide parents with access to an insurance hotline phone and a list of the local insurance providers’ contact information to address insurance concerns regarding vaccine coverage while they are in the office for their appointment. Finally, making all ancillary staff in the office aware that vaccination is a priority can be helpful. They can help to further spread the message of the importance of immunization.

Barriers related to attitudes

Attitudes of parents can be a significant barrier. Regarding the HPV vaccine specifically, some parents may have moral concerns or specific fears about the vaccine. A recent study of cross-sectional data from the 2007 Health Information National Trends Survey (HINTS) identified certain factors that influenced parents’ perceptions of the HPV vaccine. 12 Results indicated that 57.5% of the parents would have their 11 to 12-year-old daughter vaccinated, 24.9% were unsure, and 17.6% said they would not have their daughter vaccinated. Of the parents who refused vaccination, 47% did so because of insufficient knowledge about the vaccine, 19.6% were worried about vaccine safety, 8.8% thought their child was not sexually active, and 5.6% said their doctor did not recommend the vaccine. Moreover, 5.4% thought their child did not need the vaccine, 3.1% thought the child was too young to receive the vaccine, 2.7% thought more research on the vaccine was needed, and 2.1% had anti-vaccine beliefs. Taken together, more than half of these reasons are related to lack of knowledge about the vaccine or lack of provider recommendation. These results underscore the critical role of the provider in recommending the HPV vaccine to their 11 to 12-year-old patients and educating the parents about the HPV vaccine and the rationale behind the recommended age range.

These issues related to attitudes of parents can be addressed by having a set of answers to commonly asked questions about the vaccine. For example, if a parent is concerned about sexual disinhibition if their child receives the HPV vaccine, the provider could use the analogy that when a law requiring seat belts was passed, no one was afraid that people would drive more recklessly. Another analogy is that people generally do not view administration of a vaccine against tetanus as an invitation to step on rusty nails. For parents who say that their child is too young to receive the HPV vaccine and they are not yet sexually active, the analogy of fluoride treatment can be used. Dental patients do not receive fluoride treatment after they have cavities; they receive it beforehand for protection against cavities.

Attitudes of adolescents can also be a barrier to immunization. For example, they may perceive a stigma associated with the HPV vaccine and worry that their peers will assume they are sexually active if they receive the vaccine. Also, due to their extracurricular activities and social schedules, they may view going to the office for vaccination as inconvenient, or they do not want a sore arm to interfere with their activities. Ways to address these barriers are to encourage the parents to convince the adolescents of the importance of immunization. The barrier of inconvenience can be overcome by making immunizations more easily available through school-based immunization programs, immunization clinics during the summer when adolescents are more accessible, and after-hours immunization appointments.

Medical providers are prone to their own biases as well. A number of studies have shown that, for some vaccines, particularly HPV, providers have a reluctance for administering this vaccine or recommending it at the earliest age groups. 13–16 Physicians must keep in mind that provider recommendation has been shown to be the most influential factor affecting parents’ decisions regarding immunization. 17 Thus, providers must be aware that their personal biases can affect their communication with patients and parents regarding immunization and their decisions on whether to recommend a particular vaccine.

Barriers related to knowledge

Lack of knowledge can also be a barrier. While most parents are in favor of vaccines, many are not aware of the fact that adolescents are a target age group for vaccination. Immunizations do not drive adolescents into the doctors office like they do for young children. One strategy to overcome this is to set up parental expectations for adolescent immunization early in the process. For example, when the child is 9–10 years of age, the provider can notify the parents of the vaccines that their child should receive when they are 11–12 years of age. Furthermore, current generations of parents and children are unaware of the potential effects of not being immunized, as they did not experience the time period when these diseases were not vaccine-preventable. Lack of awareness about the benefits of immunization, combined with compelling stories of popular figures in the media about health issues purported as being related to immunization, can create a significant barrier to immunization. Many individuals find these messages more compelling than messages from medical providers, which tend to be dry. This barrier can be overcome by trying to find compelling ways to deliver the message of the importance of immunization. Some people may be more compelled by emotional messages. Others may be more compelled by scientific facts, like graphs of incidence of HPV infection or tables about vaccine efficacy. Providing real world examples can be helpful with some people as well. For example, if a parent is concerned about adverse events of the HPV vaccine, the physician can point out that the likelihood of experiencing an adverse event from the HPV vaccine is at least 100 times less than that of getting into an automobile accident on the way home from the medical appointment. Familiarity of both reputable vaccine Web sites and anti-vaccine Web sites is also helpful for effectively communicating with parents. Discerning whether a vaccine Web site contains reliable information can be difficult for parents.

The CDC has many downloadable resources to assist in overcoming barriers to immunization. There is a pre-teen vaccine campaign containing information and materials that can be downloaded directly from the CDC Web site. 18 There is also a CDC Web site called “Some Common Misconceptions about Vaccinations and How to Respond to Them.”19

In summary, HPV infection is common in adolescents and occurs at a young age, and vaccinating patients at the youngest recommended age groups is critical to reducing the burden of HPV. There is a multitude of resources and strategies providers may utilize to assess and improve adolescent immunization rates in their practices. These strategies can be applied to other vaccines on the ACIP adolescent immunization schedule in addition to the HPV vaccine.

References

  1. CDC. YRBSS: Youth Risk Behavior Surveillance System, 2007. Available at: http://www.cdc.gov/healthyyouth/data/index.htm. Accessed January 8, 2010.
  2. Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218-226.
  3. CDC. Vaccination coverage among adolescents aged 13-17 years–United States, 2007. MMWR. 2008;57:1100-1103.
  4. Bilukha O, Rosenstein N; National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR. 2005;54(RR-7):1-21.
  5. Broder KR, Cortese MM, Iskander JK, et al. Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2006;55(RR-3):1-34.
  6. CDC. National, state, and local area vaccination coverage among adolescents aged 13-17 years–United States, 2008.MMWR.. 2009;58:997-1001.
  7. Healthy People 2010. Available at: http://www.healthypeople.gov. Accessed January 18, 2010.
  8. Dempsey A, Cohn L, Dalton V, Ruffin M. Patient and clinic factors associated with adolescent human papillomavirus vaccine utilization within a university-based health system. Vaccine. 2010;28:989-995.
  9. CDC. An overview of AFIX. Available at: http://www.cdc.gov/vaccines/programs/afix/default.htm. Accessed January 8, 2010.
  10. Kaplan DW. Barriers and potential solutions to increasing immunization rates in adolescents. J Adolesc Health. 2005;37:502-510.
  11. Recommendations regarding interventions to improve vaccination coverage in children, adolescents, and adults. Task Force on Community Preventive Services. Am J Prev Med. 2000;18:92-140.
  12. Fang CY, Coups EJ, Heckman CJ. Behavioral correlates of HPV vaccine acceptability in the 2007 Health Information National Trends Survey (HINTS). Cancer Epidemiol Biomarkers Prev. 2010;19:319-326.
  13. Raley JC, Followwill KA, Zimet GD, Ault KA. Gynecologists' attitudes regarding human papillomavirus vaccination: a survey of Fellows of the American College of Obstetricians and Gynecologists. Infect Dis Obstet Gynecol. 2004;12:127-133.
  14. Mays RM, Zimet GD. Recommending STI vaccination to parents of adolescents: the attitudes of nurse practitioners. Sex Transm Dis. 2004;31:428-432.
  15. Kahn JA, Zimet GD, Bernstein DI, et al. Pediatricians' intention to administer human papillomavirus vaccine: the role of practice characteristics, knowledge, and attitudes. J Adolesc Health. 2005;37:502-510.
  16. Riedsel JM, Rosenthal SL, Zimet GD, et al. Attitudes about human papillomavirus vaccine among family physicians. J Pediatr Adolesc Gynecol. 2005;18:391-398.
  17. Keane MT, Walter MV, Patel BI, et al. Confidence in vaccination: a parent model. Vaccine. 2005;23:2486?2493.
  18. CDC. Pre-teen vaccine campaign. Available at: http://www.cdc.gov/vaccines/spec-grps/preteens-adol/07gallery/default.htm. Accessed January 8, 2010.
  19. CDC. Some common misconceptions about vaccination and how to respond to them. Available at: http://www.cdc.gov/vaccines/vac-gen/6mishome.htm. Accessed January 8, 2010.

Discussion

How long can HPV persist?

Amanda Frisch Dempsey, MD, PhD, MPH: HPV can persist for years—especially high-risk HPV types. The length of persistence correlates with the risk for the development of cancer.

Do condoms prevent transmission of HPV to any extent?

Dempsey: HPV is an epithelial virus and is transmitted by close “skin-to-skin” contact. Condoms leave some skin uncovered that may be shedding HPV, which means the infection could be transmitted even when condoms are used. Thus condoms prevent the transmission of HPV to some extent, but not completely.

Kenneth A. Alexander, MD, PhD: There is a compelling body of data showing that, in women who have cervical cytological abnormalities, when their partners reliably use condoms, the rate of spontaneous resolution of Pap test abnormalities increases substantially.

Is there any observed link between anal sex between men and HPV infections?

Dempsey: Yes—men who have sex with men (MSM) are at higher risk of developing anal complications from HPV infection, such as anal precancers and cancer, than non-MSM.

Are there any data regarding an association between oral sex and an increased risk for HPV-related cancers?

Dempsey: I believe some emerging data indicate that the number of oral sex partners is related to risk for developing certain types of head and neck cancer, although I am not sure whether this is different for MSM vs non-MSM when the number of partners is the same.

Can HPV be detected in asymptomatic males?

Dempsey: HPV DNA can be detected in males, but there is not yet agreement as to what the standard should be for collecting the sample for testing. Test results vary depending on how the sample is collected, and no consensus exists for sample collection.

How long does the HPV vaccine protect if it is started at 9 years?

Dempsey: Data in older women have shown that vaccine protection can last more than 6 years. Because the immune response is even higher in younger patients who are vaccinated, we assume that a 9-year-old who has been vaccinated will have at least this duration of immunity. In all likelihood, the actual duration of immunity (regardless of age) will be much longer than 6 years, but this remains to be proven.

How important are antibody titers in protection against HPV disease?

Alexander: In the case of HPV, it is not clear whether there is a correlation between vaccine efficacy and antibody titers. Indeed, there is no correlation between a woman’s HPV antibody titer and her ability to clear an HPV infection. Furthermore, children who are agammaglobulinemic do not experience complications with HPV infection, whereas individuals who lack cellular immunity do. This said, pre-clinical trials demonstrated that administering a dose of immunoglobulin derived from an HPV pseudovirion-vaccinated animal to another animal conferred protection against HPV infection. I suspect that it is not simply antibody levels that determine HPV vaccine efficacy.

Is there a potential need for a booster?

Dempsey: Not enough time has elapsed to know for sure whether or not vaccine recipients will need a booster. Based on the structure of the vaccine, which is similar to the hepatitis B vaccine, there is an expectation that a booster will not be needed for the HPV vaccine. The immunogenicity of the vaccine has been shown to be stable for more than 6 years according to available data, but more time is needed to answer the question of whether a booster will be needed for the HPV vaccine.

Alexander: In a study examining the effects of a booster dose after 5 years, the antibody levels that were achieved exceeded those of the primary series. 1 This indicates that the HPV vaccine induces significant T-cell memory and a booster dose would be effective if time indicates it will be needed. Nonetheless, the marked booster effect seen in clinical trials suggests that the quadrivalent vaccine is a potent inducer of T-cell memory. Such induction of T-cell memory is a hallmark of a durable vaccine.

What is the significance of the different adjuvants of the HPV vaccines?

Dempsey: There are no specific data demonstrating whether one adjuvant is more effective than the other.

Could vaccinating promote clearance in one already infected with a vaccine strain?

Dempsey: This is a prophylactic vaccine. The vaccine is not therapeutic and has no known effect on infections already established. This is supported by data from clinical trials that have formally sought to address this question.

Why does the bivalent vaccine seem to be associated with cross-protection against 3 HPV types, whereas the quadrivalent vaccine appears to offer cross-protection against only 1 type?

Alexander: One possible explanation is that, in the studies examining cross-protection of the quadrivalent vaccine, the prevalence of HPV disease in the population was approximately 1.5 times that of the population analyzed in the bivalent vaccine study. Moreover, the differences in cross-protection between the 2 vaccines may not be substantial.

Does the bivalent vaccine cause fewer adverse events because it has one-half the HPV subtypes as the quadrivalent vaccine? If not, why would the bivalent vaccine be chosen?

Alexander: The rates of adverse events that occur with administration of the vaccines are similar; however, these effects have never been compared directly in the same study.

Dempsey: Some hypothesize that the adjuvant in the bivalent vaccine is superior to that of the quadrivalent vaccine and is therefore more likely to provide longer term immunity. However, this remains to be proven. At this point, the only conclusions that can be made are that the 2 vaccines seem basically equivalent in their ability to prevent HPV 16/18-related infections and diseases.

Is there a concern for the development of deep vein thrombosis (DVT) following HPV vaccination?

Alexander: DVT has occurred in vaccinees just as it has occurred in non-vaccinees. The occurrence of DVT is a consequence of the population being immunized: reproductive-age females, many of whom are on oral contraceptives, and many of whom smoke. The statistical association of DVT, smoking, and oral contraceptive use is well established. The rate of DVT is not higher in vaccinees. When the HPV vaccine is administered to female patients, they should be advised to never start smoking, and if they already smoke, they should be given help to quit.

Will strain replacement be observed after administration with HPV vaccines, as it was with the pneumococcal vaccine?

Alexander: In pneumococci, competition is often observed between strains. In other words, more than 1 pneumococci strain simultaneously colonizing in the nasopharynx is unusual. In contrast, mixed infection with multiple HPV strains is often the rule rather than the exception. Thus, it appears that HPV strains do not compete with each other in the way pneumococcal strains do. Consequently, eliminating an HPV strain with a vaccine may not necessarily set the stage for increased prevalence of another HPV strain. However, only time will tell if this is indeed the case.

Should an individual still be immunized against HPV even if they have been sexually active for many years or if they already have been infected (eg, present with a genital lesion)?

Dempsey: In both cases the individual should still be immunized. Although the vaccine would not protect against the HPV type that has already infected the individual, it would provide protection against the other HPV types and therefore would likely be of some benefit.

Are there concerns of autoimmune disease or idiopathic arthritis relative to the vaccine?

Dempsey: There has been ongoing monitoring and formal evaluations of the vaccine’s safety. Thus far, the vaccine has not been linked to any diseases or serious adverse events.

What is the disadvantage of not implementing the HPV vaccine series until the adolescent is 13–15 years of age, rather than immunizing at the recommended age range of 11–12 years?

Dempsey: There are many reasons vaccination should not be postponed. I point out to parents that it is best to give this vaccine well before a child may even begin thinking about becoming sexually active. Administering this vaccine to 11 to 12-year-old children may actually remove the idea that it is linked to sexual activity. No one suspects that their 11-year-old child may be sexually active, but many parents may fear that their 15-year-old child is sexually active. Implementation at a younger age removes the links between the HPV vaccine and morality and sexual issues that are more apparent when the patient is an adolescent. Another reason I give to parents who seem particularly reluctant is that not all sexual activity is consensual, and the HPV vaccine would confer an extra level of protection in those circumstances.

Recently, new guidelines put forth by the American College of Obstetricians and Gynecologists recommend that women should not have their first Pap test before the age of 21 years. How will that change the way we will think about what we are going to observe as pediatricians?

Dempsey: I believe these new guidelines add to the importance of administering the HPV vaccines as early as possible. Although rare, invasive disease can happen among adolescents, and those few cases will be missed if Pap tests are not performed until the age of 21. Therefore, doing everything possible to improve or maximize prevention is key.

Alexander: I believe pediatricians will see genital warts.

What is the rationale for these new guidelines?

Dempsey: As we learn more about the natural history of HPV infection, we have come to the understanding that it is very rare for an adolescent to develop high-grade cervical lesions/cervical cancer. However, it is very common for adolescents to develop low-grade lesions that will disappear spontaneously, without any clinical adverse effects. Taken as a whole, it was believed that the morbidity/risks associated with following up on all of the low-grade lesions that were likely to resolve on their own anyway outweighed the miniscule risk of high-grade cervical changes/cancer during adolescence. This recognition led to changes in Pap testing guidelines. Essentially it is now believed that early Pap testing would do more harm than good.

Why stop vaccinating at 26 years of age? For example, if a 60-year-old may live to be 90 years of age, why not protect that patient from cancers (eg, laryngeal cancer) as well as STDs?

Dempsey: As age increases, the likelihood that a person has not been exposed to the HPV types found in the vaccine decreases, so the potential benefits to receiving the vaccine, in general, wane as a person ages. However, this does not account for the variability in risk that occurs at an individual level—for example if someone has had no sexual activity until age 50 and then becomes sexually active. An additional reason for the current age limitations is that the initial clinical trial data included women up to age 26, which was the basis of the ages of licensure. However, data are now available for women up to age 45, and HPV vaccines are licensed in some countries up to that age. There have been no published studies on the effectiveness of the HPV vaccine beyond age 45, so one can only estimate the level of effectiveness of the vaccine among older individuals.

Since we vaccinate mostly teens/pre-teens, how do the immunogenicity and adverse events compare between boys and girls vs men and women?

Dempsey: Immunogencity is higher the younger you are, for both men and women.

Alexander: Adverse event rates are essentially the same in all populations studied.

Are we supposed to use either HPV vaccine alone to complete the series or can we interchange to finish the series (eg, if there is a shortage of 1 of the vaccines)?

Dempsey: No. The same type of vaccine should be used for all 3 doses.

Should pediatricians routinely administer the HPV vaccine to 9-year-olds or 11-year-olds in their practice?

Dempsey: I would leave it to parent preference and the judgement of the provider. If the 9-year-old is not considered high- risk, then vaccinating at the age of 11 (the target age for vaccination) is probably sufficient.

Alexander: A truism of immunization is that a dose of vaccine that is delayed is a dose that is not given.

If a patient receives only 1 or 2 doses of the HPV vaccine and does not return to your office for another year, is it necessary to restart the full series?

Dempsey: There has not been any indication that prolonging the vaccination schedule is harmful or results in reduced immunity; however, as more time passes between doses, the risk of exposure to HPV when the vaccine is not fully protective increases.

Reference

  1. Olsson SE, Villa LL, Costa RL, et al. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine. 2007;25:4931-4939.